The present invention relates to medicinal aerosol products and, in particular, to aerosol products such as metered dose inhalers for delivery of steroids. The invention is particularly related to certain 20-ketosteroids that have been found to be highly susceptible to chemical degradation when formulated as solution aerosol products, and provides a way of enhancing chemical stability of such steroids.
Structure I shown below is a typical core structure for a large number of natural and synthetic 20-ketosteroids, with the standard IUPAC numbering system of the carbon positions 1 to 21 indicated. 
These types of steroids, with varying substituents and bonding, have many well-known therapeutic uses, especially based upon their anti-inflammatory activity. It is often desirable to deliver such steroids topically using aerosol spray devices, such as metered dose inhalers (MDIs). MDIs are commonly used to deliver steroids, e.g., beclomethasone dipropionate, to the airways of patients via oral or nasal inhalation for the treatment of asthma and allergic rhinitis.
One common difficulty, however, in making products for delivering steroids has been that they are often chemically unstable in aerosol formulations and degrade during storage. A great deal of research has been directed at steroid degradation. Chemical degradation is especially problematic when the steroid is dissolved in the formulation and, consequently, the vast majority of marketed MDI steroid products are formulated as particulate suspensions of the steroid, which are much less susceptible to chemical degradation than solutions. For example, it is believed that all currently marketed CFC-containing MDI products for delivering steroids are available only as particulate suspension formulations in CFC propellants.
More recently, some selected steroids have been reformulated as solutions in non-CFC hydrofluorocarbon (HFC) propellants with ethanol. In the case of beclomethasone dipropionate, for example, solution formulations are disclosed in U.S. Pat. No. 5,766,573 which are surprisingly chemically stable in propellant HFC 134a and/or 227 and ethanol in a conventional aluminum canister. Likewise, ciclesonide formulations are surprisingly chemically stable in certain solution MDI formulations disclosed in WO98/52542. Solution formulations of flunisolide are disclosed in U.S. Pat. No. 5,776,433, where it is indicated that chemical stability may be enhanced by using additives like water, sorbitan trioleate, and cetylpyridinium chloride, and also that certain containers such as glass and resin coated aluminum enhance chemical stability and/or minimize the absorption of flunisolide onto the container wall. Also, WO96/40042 discloses that aqueous formulations of triamcinolone acetonide in neutral or basic solutions undergo oxidative degradation catalyzed by trace levels of metal ions, especially copper, and proposes the use of EDTA as sequestering agent and/or adjusting pH.
Despite these limited examples, though, most commercial MDI formulations of steroids and other drugs have continued to be particulate suspensions. WO98/13031, for example, discloses recent work on reformulating budesonide as a non-CFC suspension formulation. However, suspension formulations of a medicament are more likely to encounter problems with physical instability (e.g., agglomeration, crystal growth and deposition on the container wall, all resulting in inconsistent dosage delivery).
A drug delivery device providing medicinal steroid solution formulations with enhanced chemical stability would offer some significant advantages over suspension formulations. Besides homogeneity, solution formulations have been found in some casesxe2x80x94e.g., using HFC propellants and low ethanol contentxe2x80x94to give dramatically higher respirable fractions (i.e., the percentage of active ingredient able to reach the airways of the lung) compared to a particulate suspension of the steroid drug. See U.S. Pat. No. 5,776,432. Furthermore, an aerosol product providing a chemically and physically stable aerosol steroid formulation using non-CFC propellant would offer the advantage of being more ozone friendly than currently available aerosol products with CFCs.
Nevertheless, despite a substantial need, the problem of chemical degradation in steroid solution aerosol products has been poorly understood. Until now there has been no way to identify which steroids are likely to be most stable as solution aerosols and which will be most sensitive to degradation in solution aerosol products or how to reduce such degradation.
It has now been found that those steroids in particular having a C-20 ketone and an OH group at the C-17 position or, especially, the C-21 position or both (hereafter collectively referred to as xe2x80x9cC-17/21 OH 20-ketosteroidsxe2x80x9d) are subject to enhanced chemical degradation when stored in contact with a metal container (particularly the metal oxide e.g., Al2O3 layer that forms on the interior surface of the container). Moreover, the vast majority of MDI""s on the market, including all MDI steroid products, use aerosol containers made of metal, usually aluminum. By utilizing an aerosol container having a non-metal interior surface it is possible to produce solution aerosol formulations of C-17/21 OH 20-ketosteroids having enhanced chemical stability.
Generic structures for typical C-17 OH, C-21 OH, and C-17 and 21 OH 20-ketosteroids are shown below in structures II-IV, respectively. 
The present invention is especially preferred with respect to C-21 OH 20-ketosteroids (with or without a C-17 OH group). The C-21 OH group can substantially increase biological activity of a steroid, but such steroids are also much more susceptible to chemical degradation in the presence of metal. Particularly preferred 20-ketosteroids are budesonide, triamcinolone acetonide, dexamethasone, and betamethasone 17-valerate, all of which have an OH group at the C-21 position. These steroids are all currently on the market as CFC particulate suspension formulations in metered dose inhalers and, at least in the case of budesonide, work has been conducted to reformulate this important steroid as a non-CFC suspension product in HFA propellants. See PCT published application WO98/13031.
The most preferred type of container for use in the present invention is a conventional aluminum (or aluminum alloy) aerosol canister, but with an interior coating of an inert material, such as a spray-coated, baked epoxy-phenolic lacquer (available from Cebal Printal U.K. Ltd.). Other metals, such as stainless steel, may likewise be used with an inert interior coating. It is also preferred that the internal surfaces of metal valve components in contact with the formulation are similarly coated with an inert material. Another preferred coating for the inside of the container is perfluoroethylenepropylene (FEP).
A preferred coating for the metal valve components is a very thin layer of glass, or other material, deposited by gas vapor deposition. Such coating is preferably used on all of the metal valve components in contact with the formulation, including the inside and outside of the metering chamber, inside and outside of the bottle emptier (if any), and the inside and outside of the valve stem (if metal), and may also be used to coat the inside of the canister. The preferred such coating technique is the Silcosteel(trademark) process available from Restek Corporation, Bellefonte, Pa. The Silcosteel(trademark) aspect of the invention is useful even outside the context of the chemical degradation problem, for both solution and suspension formulations.
Preferred formulations use a liquified propellant such as hydrogen-containing (non-CFC) propellants, more preferably hydrofluorocarbons, such as 134a and/or 227. Particularly preferred formulations include about 0.1 to 0.5% C-17/21 OH 20-ketosteroid about 75 to 99% 134a and/or 227, and about 1 to 25% w/w ethanol, more preferably about 80 to 95% 134a and/or 227, and about 5 to 20% ethanol. The most preferred medicinal aerosol products according to the invention are MDI""s comprising about 0.1 to 0.5% budesonide or triamcinolone acetonide dissolved in about 80-95% 134a and/or 227 and about 5-20% ethanol, contained in a coated aluminum aerosol canister equipped with a metering valve.
It should also be noted that chemical stability is especially critical for MDIs since these medicinal aerosol products must remain stable and deliver accurate dosing throughout their shelf life (typically 2 to 3 years) and in use. Only a very small amount of chemical degradation can be tolerated. Moreover, by providing chemically stable solutions of C-17/21 OH 20-ketosteroids, such as budesonide, triamcinolone acetonide, dexamethasone, and betamethasone 17-valerate, MDIs can be made that produce extra-fine aerosols resulting in higher respirable fractions than suspension formulation products.
It can thus be seen that the present invention provides a medicinal aerosol steroid solution formulation product with enhanced chemical stability. Such product includes a container equipped with a dispensing valve and containing a medicinal aerosol formulation having a 20-ketosteroid drug dissolved therein. The 20-ketosteroid is other than flunisolide and has an OH group at the C-17 or C-21 position or both, and the container is provided with a non-metal interior surface so as to reduce chemical degradation.
Also provided is a method of reducing the chemical degradation of a medicinal 20-ketosteroid dissolved in a formulation contained in a metal container, said 20-ketosteroid being other than flunisolide and having an OH group at the C-17 position or C-21 position or both, comprising the step of providing a coating of inert material on the interior surface of the metal container so as to reduce reaction of the 20-ketosteroid with metal oxides from the container.
The invention further provides a process for making a chemically stable 20-ketosteroid solution aerosol product, by filling into a container an aerosol formulation comprising a dissolved 20-ketosteroid other than flunisolide, said 20-ketosteroid having an OH group at the C-17 position or C-21 position or both, and said container having an inert non-metal interior surface so as to avoid chemical degradation of the 20-ketosteroid due to interaction with the container.